Discovery of the salicylaldehyde-based compound DDO-02267 as a lysine-targeting covalent inhibitor of ALKBH5.

N-methyladenosine (mA) is a crucial mRNA epigenetic modification in eukaryotes, and its methylation regulation is associated with the proliferation and metastasis of diverse tumor cells. ALKBH5 functions as a demethylase for mA and plays a role in the demethylation process, thus influencing tumor cell growth and migration. However, there are limited reports on selective small molecule inhibitors of ALKBH5.

Discovery of Pyrazolo[1,5-]pyrimidine Derivative as a Novel and Selective ALKBH5 Inhibitor for the Treatment of AML.

MA (-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers.

Proton pump inhibitors selectively suppress MLL rearranged leukemia cells via disrupting MLL1-WDR5 protein-protein interaction.

Genetic rearrangements of the mixed lineage leukemia (MLL) leading to oncogenic MLL-fusion proteins (MLL-FPs). MLL-FPs occur in about 10% of acute leukemias and are associated with dismal prognosis and treatment outcomes which emphasized the need for new therapeutic strategies. In present study, by a cell-based screening in-house compound collection, we disclosed that Rabeprazole specially inhibited the proliferation of leukemia cells harboring MLL-FPs with little toxicity to non-MLL cells.

Targeting protein-protein interaction between MLL1 and reciprocal proteins for leukemia therapy.

The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia.

Design, synthesis, and initial evaluation of affinity-based small molecular probe for detection of WDR5.

WDR5, a subunit of the SET/MLL complex, plays critical roles in various biological progresses and are abnormally expressed in many cancers. Here we report the design, synthesis, and biochemical characterization of a new chemical tool to capture WDR5 protein. The probe is a biotinylated version of compound 30 that is a potent WDR5 inhibitor we previously reported.

Discovery, design and synthesis of 6H-anthra[1,9-cd]isoxazol-6-one scaffold as G9a inhibitor through a combination of shape-based virtual screening and structure-based molecular modification.

Protein lysine methyltransferase G9a is widely considered as an appealing antineoplastic target. Herein we present an integrated workflow combining shape-based virtual screening and structure-based molecular modification for the identification of novel G9a inhibitors. The shape-based similarity screening through ROCS overlay on the basis of the structure of UNC0638 was performed to identify CPUY074001 contained a 6H-anthra[1,9-cd]isoxazol-6-one scaffold as a hit.

Structure-based design of ester compounds to inhibit MLL complex catalytic activity by targeting mixed lineage leukemia 1 (MLL1)-WDR5 interaction.

WDR5 is an essential protein for enzymatic activity of MLL1. Targeting the protein-protein interaction (PPI) between MLL1 and WDR5 represents a new potential therapeutic strategy for MLL leukemia. Based on the structure of reported inhibitor WDR5-0103, a class of ester compounds were designed and synthetized to disturb MLL1-WDR5 PPI.

High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity.

MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction.

A Double-Lobe Flap Design Combined Nasolabial Advancement and Infraorbital Rotation for Reconstruction of Infraorbital Defect.

Various adjacent flaps have been designed to close infraorbital defect, and each of them is trying to get an aesthetic outcome and meanwhile circumvent eyelid retraction, ectropion, and functional disability. Here, the authors report an adjacent double-lobe flap, which took advantage of nasolabial advancement and infraorbital rotation of the 2 lobes, combinatorially closed a pentagon infraorbital defect by removal of 2 small skin paddles as donor sites, and finally yielded an acceptable aesthetic and functional outcome. This flap may be a new option for closure of polygon infraorbital defects.

G9a - An Appealing Antineoplastic Target.

Background: G9a is the primary enzyme for mono- and dimethylation at Lys 9 of histone H3 and forms predominantly the heteromeric complex as a G9a-GLP (G9a-like protein) that is a functional histone lysine methltransferase in vivo. Mounting evidence suggests that G9a catalyzes methylation of histone and nonhistone proteins, which plays a crucial role in diverse biological processes and human diseases.

Methods: In this study, the current knowledge on biological functions of G9a and inhibitors were summarized.

Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5.

MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.

CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells.

Heat-shock protein 90 (Hsp90) is highly expressed in many tumor cells and is associated with the maintenance of malignant phenotypes. Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound CPUY201112 as a potent Hsp90 inhibitor.

Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor.

Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1-Nrf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure-activity and structure-property relationships of the ring systems to improve the drug-like properties. Compound 18e, which bore p-acetamido substituents on the side chain phenyl rings, was the best choice for balancing PPI inhibition activity, physicochemical properties, and cellular Nrf2 activity.

Hybrids of the Benzofuran Core from Natural Products and the 2,4-Dihydroxy-5-isopropylbenzene Fragment as Potent Hsp90 Inhibitors: Design, Synthesis and Bioevaluation.

Several chemical fragments have been confirmed as highly efficient cores for the design of Hsp90 inhibitors. Molecular hybridization of potent fragments has been widely used as a rational drug discovery strategy. In this study, a novel class of hybrids of benzofuran, a privileged core from natural products, and 2,4-dihydroxy-5-isopropyl phenyl, an efficient fragment in Hsp90 inhibitors, were designed and synthesized.

Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.

Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h).

Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through Shape-Based Similarity Screening.

Hsp90 as a promising therapeutic target for the treatment of cancer has received great attention. Many Hsp90 inhibitors such as BIIB021 and CUDC-305 have been in clinical. In this paper shape-based similarity screening through ROCS overlays on the basis of CUDC-305, BIIB021, PU-H71 and PU-3 were performed to discover HSP90 inhibitors.

Synthesis and evaluation of a novel class Hsp90 inhibitors containing 1-phenylpiperazine scaffold.

Previously, we identified 1-(2-(4-bromophenoxy)ethoxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol (1) as a novel Hsp90 inhibitor with moderate activity through virtual screening. In this study, we report the optimization process of 1. A series of analogues containing the 1-phenylpiperazine core scaffold were synthesized and evaluated.

Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis.

Keap1 is known to mediate the ubiquitination of Nrf2, a master regulator of the antioxidant response. Directly interrupting the Keap1-Nrf2 interaction has been emerged as a promising strategy to develop novel class of antioxidant, antiinflammatory, and anticancer agents. On the basis of the molecular binding determinants analysis of Keap1, we successfully designed and characterized the most potent protein-protein interaction (PPI) inhibitor of Keap1-Nrf2, compound 2, with K(D) value of 3.

Insight into the intermolecular recognition mechanism between Keap1 and IKKβ combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation.

Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1), a substrate adaptor component of the Cullin3 (Cul3)-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2) and IκB kinase β (IKKβ), which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI), the intermolecular recognition mechanism of Keap1 and IKKβ has been poorly investigated.

3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones as potent Nrf2/ARE inducers in human cancer cells and AOM-DSS treated mice.

Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation, and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1, and nuclear translocation of Nrf2 in HCT116 cells.

Effective screening strategy using ensembled pharmacophore models combined with cascade docking: application to p53-MDM2 interaction inhibitors.

Protein-protein interactions (PPIs) play a crucial role in cellular function and form the backbone of almost all biochemical processes. In recent years, protein-protein interaction inhibitors (PPIIs) have represented a treasure trove of potential new drug targets. Unfortunately, there are few successful drugs of PPIIs on the market.

Synthesis and bioevaluation of a series of α-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I).

When exposed to electrophiles, human colorectal cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel α-pyrone compound 1 as a hit. 2 with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure-activity relationship (SAR) study.

Identification, design and bio-evaluation of novel Hsp90 inhibitors by ligand-based virtual screening.

Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits.

Novel IKKβ inhibitors discovery based on the co-crystal structure by using binding-conformation-based and ligand-based method.

IκB kinase β (IKKβ), an attractive anti-inflammation and anti-cancer target, plays a crucial role in the activation of NF-κB signalling pathway. To identify novel IKKβ inhibitors, we combined structure-based and ligand-based methods based on the co-crystal structure of IKKβ. According to the chemical similarity, 162 reported IKKβ inhibitors were divided into five classes.

Synthesis and evaluation of gambogic acid derivatives as antitumor agents. Part III.

Gambogic acid (GA) has been reported as a potent apoptosis inducer. Previously, we have reported chemical modification at C(34) and C(39) of GA, leading to some agents with improved activity. To investigate the further structure-activity relationship (SAR) and preliminary mechanism of GA activity, a series of derivatives with modified prenyl side chains of GA were synthesized and evaluated.